Among the many mysteries of human biology is why complex diseases like diabetes, high blood pressure and psychiatric disorders are so difficult to predict and, often, to treat. An equally perplexing puzzle is why one individual gets a disease like cancer or depression, while an identical twin remains perfectly healthy.
Now scientists have discovered a vital clue to unraveling these riddles. The human genome is packed with at least four million gene switches that reside in bits of DNA that once were dismissed as “junk” but that turn out to play critical roles in controlling how cells, organs and other tissues behave. The discovery, considered a major breakthrough, has enormous implications because many complex diseases appear to be caused by tiny changes in hundreds of gene switches.
The findings are the fruit of an immense federal project, involving 440 scientists from 32 labs around the world. As they delved into the “junk” — parts of the DNA that are not actual genes containing instructions for proteins — they discovered it is not junk at all. At least 80 per cent of it is active and needed.
The result is an annotated road map of much of this DNA, noting what it is doing and how. It includes the system of switches that control which genes are used in a cell and when they are used, and determine, for instance, is a cell becomes a liver cell or a neuron.
The findings have immediate applications for understanding how alterations in the non-gene parts of DNA contribute to human diseases, which may in turn lead to new drugs. They can also help explain how the environment can affect disease risk. In the case of identical twins, small changes in environmental exposure can slightly alter gene switches, with the result that one twin gets a disease and the other does not.
“It’s Google maps,” said Eric Lander, president and founding director of the Broad Institute of Harvard and the Massachusetts Institute of Technology. Its predecessor, the Human Genome Project, which determined the entire sequence of human DNA, “was like getting a picture of earth from space,” he said. “It doesn’t tell you where the roads are, it doesn’t tell you what traffic is like at what time of the day, it doesn’t tell you where the good restaurants are, or cities or rivers.”
“Now you can follow the roads and see the traffic circulation. That’s exactly the same way we will use these data in cancer research.” Encode, for Encyclopedia of DNA Elements, provides a road map with traffic patterns for alternate ways to go after cancer genes, he said.
The discoveries were published on Wednesday in six papers in the journal Nature and in 24 papers in Genome Research and Genome Biology. In addition, The Journal of Biological Chemistry is publishing six review articles and Science is publishing yet another article.
In one of the Nature papers, researchers link the gene switches to a range of human diseases — multiple sclerosis, lupus, rheumatoid arthritis, Crohn’s disease, celiac disease — and even to traits like height. In large studies over the past decade, scientists found that minor changes in DNA sequences increase risk that a person will get those diseases. But those changes were in the junk, now often referred to as the dark matter — they were not changes in genes — and it was not clear what their significance was.